Expert Point of View: Andrés Cervantes, MD, PhD

The proportion of patients randomized to chemotherapy plus bevacizumab who never got cetuximab could be of importance in interpreting these results.

—Andrés Cervantes, MD, PhD

Chemotherapy plus a biologic is a ‘must’ in the first-line setting, though the best combination may not yet be proven.

—Fortunato Ciardiello, MD, PhD

During a special session at the European Society for Medical Oncology (ESMO) 2014 Congress, additional analyses from the FIRE-3 and Cancer and Leukemia Group B ­(CALGB)/SWOG 80405 trial were presented, and an expert panel was charged with putting the findings into context.

Role of Subsequent Treatment

Andrés Cervantes, MD, PhD, of University Hospital of Valencia, Spain, said the discordant overall survival results between the trials cannot be understood without detailed information on subsequent therapies. “In particular, the proportion of patients randomized to chemotherapy plus bevacizumab ­[Avastin] who never got cetuximab ­[Erbitux] could be of importance in interpreting these results,” he said.

“In a setting where more than 80% of patients get second-line therapy, it could imply that the sequence of treatments would not be relevant for overall survival. However, if the proportion of patients missing cetuximab in the second line is higher, the sequence of treatments could be very relevant,” he indicated.

Dr. Cervantes also questioned the relevance of the higher response rate with cetuximab-containing regimens, and he called on the CALGB/SWOG investigators to analyze their data with respect to depth of response and early tumor shrinkage.

Three Questions

Alberto Sobrero, MD, of San Martino Hospital, Genoa, Italy, tried to square the findings with three questions: Are the data true? Are they relevant? And are they practice changing?

“I analyzed the new data in light of five stories we already have in advanced colorectal cancer, for anti-VEGF and anti-EGFR agents,” he said.

Reviewing published data from other studies, Dr. Sobrero concluded, “The bevacizumab story in first line is very strong and convincing. The anti-EGFR story in third line is very strong and convincing. The anti-EGFR story in first-line KRAS wild-type is less convincing. The anti-EGFR story in first-line RAS wild-type is convincing as compared to chemotherapy. And the anti-EGFR story in first-line RAS wild-type is convincing, vs bevacizumab,” he said.

“That was the data up to now. Now we have new data,” he said. He found the FIRE-3 data “easy to interpret” and to have “strong internal consistency,” while finding the CALGB/SWOG data less so. Regarding both trials, Dr. Sobrero said he would “wait for the complete data before challenging these strong stories.”

Decision-Making Still Complex

Dirk Arnold, MD, PhD, of the Klinik fuer Tumorbiologie, Freiburg, Germany, commented on the emerging use of the RAS mutation as a biomarker. He noted that any RAS mutation is a negative predictive biomarker that eliminates candidates for anti-EGFR antibodies. “But the question is whether signals are so strong that we could potentially … say that not only does a negative biomarker exist—RAS mutation—but wild-type RAS may be a positive predictive marker for the anti-EGFR antibodies and may indicate patients for whom an anti-­EGFR antibody is preferable,” he said.

That said, how convincing are all the data taken together? The CALGB/SWOG trial found no difference between the biologics, but cetuximab came out ahead in FIRE-3, as did panitumumab (Vectibix) in the PEAK trial. “But PEAK was a phase II trial, and both FIRE-3 and PEAK failed their respective endpoints and had overall survival only as a secondary endpoint. Therefore, the evidence of a survival benefit cannot be viewed as particularly strong,” he added.

“The only trial with an appropriate design was CALGB/SWOG 80405, which showed a modest improvement with cetuximab. But in all the trials, the hazard ratios were below 1.0, and we must agree there’s something there,” Dr. Arnold suggested. “It may be about extent of benefit. FIRE-3 may be overstating it, and ­CALGB may be understating it.”

“The data are somewhat in line with the thought that patients with wild-type RAS do slightly better with an anti-­EGFR antibody, but there are many open questions,” he continued. While one might question why the outcomes were different in the two trials, one might also question whether having further information on treatment characteristics “will change our clinical view of the data. I doubt it.”

Decision-making in metastatic colo­rectal cancer “remains complex,” requiring clinical characteristics, treatment aims, and molecular information. A greater understanding of molecular subtypes and further refinement of this heterogeneous population beyond RAS testing will lead to treatment advances, he said.

Meanwhile, expanded RAS testing is a prerequisite for any use of an anti-EGFR antibody, and for RAS wild-type patients, any chemotherapy/antibody combination is appropriate. Selection should take into account clinical factors and patient preferences. “We balance all factors. That is the art of oncology,” Dr. Arnold remarked.

Two Good Options

Fortunato Ciardiello, MD, PhD, of Second University of Naples, Italy, said the studies demonstrate that “patients with RAS wild-type cancer have two good therapeutic options that should be offered sequentially in the first and second line—FOLFOX [leucovorin, fluorouracil (5-FU), oxaliplatin] or FOLFIRI [leucovorin, 5-FU, irinotecan] plus either an anti-EGFR monoclonal antibody or bevacizumab.”

He continued, “In my opinion, FOLFIRI or FOLFOX with an anti-EGFR antibody is the preferred first-line choice if tumor shrinkage is a relevant therapeutic goal.” This includes high tumor burden, symptomatic disease, potential conversion to surgical resection of liver metastases or, possibly, of the primary tumor.

“Tolerability, side effects, and informed discussion with the patient could be important aspects for first-line choices,” Dr. Ciardiello suggested.

He called for research on the role of maintenance and the reintroduction of chemotherapy, appropriate sequencing of bevacizumab and anti-­EGFR antibodies, and strategies to prevent or overcome acquired resistance to these biologics. “Whereas FIRE-3 data should be considered the final results of this trial, CALGB/SWOG research is still a work in progress, and we will get important information in the near future when additional analyses are completed,” he said.

Meanwhile, he concluded, “Chemotherapy plus a biologic is a ‘must’ in the first-line setting, though the best combination may not yet be proven.” ■

Disclosure: Drs. Cervantes and Arnold reported no potential conflicts of interest. Dr. Sobrero has served on advisory boards and as a speaker for Roche, Merck, Sanofi, Bayer, Amgen, Celgene, and Lilly. Dr. Ciardiello has received honoraria and/or research funds from Merck Serono, Roche, AstraZeneca, Bayer, and Astellas.